Cardiac Function and Serum Biomarkers throughout Staged Fontan Palliation: A Prospective Observational Study.

Fontan patients undergo multiple cardiothoracic surgeries in childhood. Following these procedures, ventricular function is temporarily decreased, and recovers over months. This is presumably related to cardiopulmonary bypass, but this is incompletely understood. Throughout the Fontan palliation, cardiac function is also affected by volume unloading. We aimed to gain insight into the biological processes related to impaired ventricular function and recovery following Fontan palliations using a panel of biomarkers. Furthermore, we described changes in ventricular function across the Fontan palliation due to volume unloading. We performed a prospective multicenter observational study in patients undergoing partial (PCPC) or total cavo-pulmonary connection (TCPC). Patients underwent assessment-including echocardiography and blood sampling-before surgery (T1), at first follow-up (T2), and 1 year after their procedures (T3). Blood samples were analyzed using a biomarker panel (OLINK CVD-III). Ninety-two biomarkers were expressed as principal components (PC) to limit multiple statistical testing. We included 32 PCPC patients aged 7.2 [5.3-10.3] months, and 28 TCPC patients aged 2.7 [2.2-3.8] years. The single ventricular longitudinal strain (SV GLS) temporarily decreased for PCPC patients at T2 (-15.1 ± 5.6 (T1) to -13.5 ± 5.2 (T2) to -17.3 ± 4.5 (T3), p < 0.047 for all differences), but not following TCPC. The serum biomarkers were expressed as 4 PCs. PC1, including biomarkers of cell-cell adhesion, was not related to any patient characteristic. PC2, including biomarkers of superoxide anion regulation, increased at T2. PC3, including biomarkers of cardiovascular development, related to the stage of Fontan palliation. PC4 was of uncertain biological or clinical significance. No PC was found that related to ventricular performance. The SV GLS was temporarily diminished following PCPC, but not following TCPC. Several biomarkers were related to post-operative stress and adaptation to the PCPC or TCPC circulation, but none were related to the outcome.

Executive functioning of patients with congenital heart disease: 45 years after surgery.

BACKGROUND: Nowadays, more than 90% of patients with congenital heart disease (CHD) reach adulthood. However, long-term impact on neurodevelopment and executive functioning in adults with CHD are not completely understood. PURPOSE: To investigate the self- and informant-reported executive functioning in adults with CHD operated in childhood. MATERIAL AND METHODS: Longitudinal study of a cohort of patients (n = 194, median age: 49.9 [46.1-53.8]) who were operated in childhood (< 15 years old) between 1968 and 1980 (median follow-up time: 45 [40-53] years) for one of the following diagnoses: atrial septal defect (ASD), ventricular septal defect (VSD), pulmonary stenosis (PS), tetralogy of Fallot (ToF) or transposition of the great arteries (TGA). Behavior Rating Inventory of Executive Function-Adult version (BRIEF-A) questionnaire was used to assess self- and informant-reported executive functioning. RESULTS: 40-53 years after surgery, the CHD group did show significantly better executive functioning compared to the norm data. No significant difference was found between mild CHD (ASD, VSD and PS) and moderate/severe CHD (ToF and TGA). Higher education, NYHA class 1 and better exercise capacity were associated with better self-reported executive functioning, whereas females or patients taking psychiatric or cardiac medications reported worse executive functioning. CONCLUSIONS: Our findings suggest favorable outcomes (comparable to normative data) regarding executive functioning in adults with CHD, both self- and informant-reported. However, further study is warranted to explore more in detail the different cognitive domains of executive functioning in these patients.

Vermamoeba vermiformis resides in water-based heater-cooler units and can enhance Mycobacterium chimaera survival after chlorine exposure.

BACKGROUND: Mycobacterium chimaera colonizes water-based heater-cooler units (HCUs), from which it can spread to patients during surgery. Vermamoeba vermiformis is a free-living waterborne amoeba, which was consistently present within HCUs. AIM: To determine whether these amoebae can be involved in the persistent presence of M. chimaera. METHODS: An in-vitro disinfection model. FINDINGS: Increased survival of M. chimaera was observed after chlorine exposure in the presence of V. vermiformis. Confocal microscopy demonstrated the intracellular presence of M. chimaera in V. vermiformis. CONCLUSION: In this way, V. vermiformis can contribute to the persistent presence of M. chimaera in HCUs. Cleaning and disinfection protocols should take this phenomenon into account.

Fate of the Arterial Origin of Major Aortopulmonary Collateral Arteries After Unifocalization.

BACKGROUND: During unifocalization procedures for pulmonary atresia with ventricular septal defect and major aortopulmonary collateral arteries, collateral arteries are either ligated or detached. Not much is known of the fate of the remaining arterial origins in the long term. Available computed tomography (CT) or magnetic resonance (MR) imaging of the intrathoracic arteries was examined to investigate possible abnormalities at the former position of the collateral arteries as well as ascending aortic diameters. METHODS: From 1989 to 2018, we performed 66 unifocalization procedures in 39 patients. One hundred and twenty-nine collateral arteries were ligated or detached. In 52% (15) of the surviving patients (with a total of 55 ligated or detached collaterals), sufficient imaging of the thoracic aorta from CT (11) and/or MR (9) was available for evaluation. RESULTS: The median interval between unifocalization procedure and imaging was 15 years (interquartile range [IQR]: 9-19 years). In 93% (14) of the scanned patients, 18 blunt ends were detected at the location of a former collateral artery. No aneurysm formation of the descending aorta was observed. The median diameter of the ascending aorta was 35 mm (IQR: 31-40 mm). During follow-up, no aortic dissection or rupture occurred. CONCLUSIONS: Aortic imaging late after unifocalization showed abnormalities in 93% of the scanned patients. Abnormalities consisted mostly of blunt ends of the former collateral artery. We recommend to include routine imaging of the aorta during late follow-up to detect eventual future abnormalities and monitor aortic diameters. Ascending aortic diameters showed slight dilatation with no clinical implications so far.

Treatment selection of early stage non-small cell lung cancer: the role of the patient in clinical decision making.

BACKGROUND: The objective of this study is to investigate the role and experience of early stage non-small cell lung cancer (NSCLC) patient in decision making process concerning treatment selection in the current clinical practice. METHODS: Stage I-II NSCLC patients (surgery 55 patients, SBRT 29 patients, median age 68) were included in this prospective study and completed a questionnaire that explored: (1) perceived patient knowledge of the advantages and disadvantages of the treatment options, (2) experience with current clinical decision making, and (3) the information that the patient reported to have received from their treating physician. This was assessed by multiple-choice, 1-5 Likert Scale, and open questions. The Decisional Conflict Scale was used to assess the decisional conflict. Health related quality of life (HRQoL) was measured with SF-36 questionnaire. RESULTS: In 19% of patients, there was self-reported perceived lack of knowledge about the advantages and disadvantages of the treatment options. Seventy-four percent of patients felt that they were sufficiently involved in decision-making by their physician, and 81% found it important to be involved in decision making. Forty percent experienced decisional conflict, and one-in-five patients to such an extent that it made them feel unsure about the decision. Subscores with regard to feeling uninformed and on uncertainty, contributed the most to decisional conflict, as 36% felt uninformed and 17% of patients were not satisfied with their decision. HRQoL was not influenced by patient experience with decision-making or patient preferences for shared decision making. CONCLUSIONS: Dutch early-stage NSCLC patients find it important to be involved in treatment decision making. Yet a substantial proportion experiences decisional conflict and feels uninformed. Better patient information and/or involvement in treatment-decision-making is needed in order to improve patient knowledge and hopefully reduce decisional conflict.

Tachyarrhythmia in patients with congenital heart disease: inevitable destiny?

The prevalence of patients with congenital heart disease (CHD) has increased over the last century. As a result, the number of CHD patients presenting with late, postoperative tachyarrhythmias has increased as well. The aim of this review is to discuss the present knowledge on the mechanisms underlying both atrial and ventricular tachyarrhythmia in patients with CHD and the advantages and disadvantages of the currently available invasive treatment modalities.

The effect of pre-operative blood withdrawal, with or without sequestration, on allogeneic blood product requirements.

UNLABELLED: A common effect of autologous blood withdrawal before cardiopulmonary bypass (CPB) is a decrease in haematocrit (Hct) and haemoglobin (Hb) content. A refinement of this technique is autologous blood withdrawal with the sequestration of platelet rich plasma (PRP) and red blood cells (RBCs). METHODS: One hundred and four patients were included in a randomized study stratified into three groups: the autologous blood withdrawal group (Group 1), the autologous blood withdrawal group with blood loss sequestration (Group 2) and the control group (Control group). In Group 1, the amount of withdrawn blood was transfused after CPB. In Group 2, the RBCs were transfused immediately after sequestration and the PRP was transfused after the termination of CPB. In the Control group, no autologous blood withdrawal was employed. The following variables were analysed: blood loss, blood products transfusion, fluid transfusion, diuresis, haematological and coagulation data and the duration of the operation and intensive care unit stay. RESULTS: We found no significant differences in peri-operative blood loss and transfused blood products among the three groups. There was a trend towards a lower amount of transfused fresh frozen plasma (FFP) for Group 1 (p =0.057) in the operation room (OR). The use of plasma expanders post-CPB was significantly higher in the Control group (p=0.024). RBCs coming from the auto-transfusion device were, for Group 1, significantly lower (p=0.007). The Hb and Hct values in Group 1, at start and end of CPB, were significantly lower (p=0.023-0.003 / 0.001-0.001, respectively). All other parameters were not significantly different. CONCLUSION: there were no significant differences between the study groups. This randomized trial shows that, although sequestration immediately after autologous blood withdrawal has no added value, autologous blood withdrawal in patients with a normal pre-operative Hb and Hct is simple, inexpensive and allows for autologous blood transfusion.

Clinical outcome and blood transfusion after infant cardiac surgery with a routine use of conventional ultrafiltration.

OBJECTIVE: Priming-related hemodilution is the culprit behind excessive body water accumulation, postoperative coagulopathy and enhanced blood transfusion in infant cardiac surgery patients. In this retrospective, observational study, clinical data were analyzed to assess the effect of conventional ultrafiltration on allogenic blood transfusion and patient clinical outcome. METHODS: All infants with a bodyweight up to 10 kg who underwent consequent cardiac surgery in 2011 and 2012 were eligible for the audit. Seventy patients, operated in accordance with existing pediatric protocol, enrolled in the control group. The study group consisted of 55 patients who were operated employing conventional ultrafiltration during bypass and recently adjusted hematocrit targets. The following variables were primarily investigated: hematocrit and colloid osmotic pressure value, total volume of blood products transfused and duration of postoperative mechanical ventilation. Secondary outcome measures were: postoperative urine production, postoperative blood loss, length of stay at the intensive care unit and hospital stay. RESULTS: There were no significant differences between the groups in relation to demographics or hematological and cardiopulmonary bypass data. The ultrafiltration volume removed from circulation during bypass in the study group was 171 ± 99 ml. No significant difference between the groups was found with regard to the total allogenic blood transfusion (study group 216 ± 92 ml versus control group 191 ±93 ml; p = 0.136). All recorded clinical end points, duration of mechanical ventilation, duration of chest tube in situ, stay in ICU and stay in hospital, were similar between the groups. CONCLUSIONS: Routine use of conventional ultrafiltration during the cardiac surgery for patients with a bodyweight less than 10 kg was a safe technique that allowed us to achieve higher hematocrit levels at the end of the operation without additional transfusions of allogenic blood. On the other hand, ultrafiltration did not improve the clinical end points.

Genetic and epigenetic determinants mediate proneness of oncogene breakpoint sites for involvement in TCR translocations.

T-cell receptor (TCR) translocations are a genetic hallmark of T-cell acute lymphoblastic leukemia and lead to juxtaposition of oncogene and TCR loci. Oncogene loci become involved in translocations because they are accessible to the V(D)J recombination machinery. Such accessibility is predicted at cryptic recombination signal sequence (cRSS) sites ('Type 1') as well as other sites that are subject to DNA double-strand breaks (DSBs) ('Type 2') during early stages of thymocyte development. As chromatin accessibility markers have not been analyzed in the context of TCR-associated translocations, various genetic and epigenetic determinants of LMO2, TAL1 and TLX1 translocation breakpoint (BP) sites and BP cluster regions (BCRs) were examined in human thymocytes to establish DSB proneness and heterogeneity of BP site involvement in TCR translocations. Our data show that DSBs in BCRs are primarily induced in the presence of a genetic element of sequence vulnerability (cRSSs, transposable elements), whereas breaks at single BP sites lacking such elements are more likely induced by chance or perhaps because of patient-specific genetic vulnerability. Vulnerability to obtain DSBs is increased by features that determine chromatin organization, such as methylation status and nucleosome occupancy, although at different levels at different BP sites.

Quality of life among patients with severe aortic stenosis.

BACKGROUND: The disease burden of patients with severe aortic stenosis is not often explored, while the incidence is increasing and many patients who have an indication for aortic valve replacement are not referred for surgery. We studied the quality of life of 191 patients with severe aortic stenosis, hypothesising that symptomatic patients have a far worse quality of life than the general population, which could enforce the indication for surgery. METHODS: The SF-36v2 Health Survey was completed by 191 consecutive patients with symptomatic or asymptomatic severe aortic stenosis. RESULTS: Asymptomatic patients (n = 59) had health scores comparable with the general Dutch population but symptomatic patients (n = 132) scored significantly lower across different age categories. Physical functioning, general health and vitality were impaired, as well as social functioning and emotional well-being. There was no relation between degree of stenosis and physical or mental health scores. CONCLUSIONS: Both physical and emotional problems have a major impact on normal daily life and social functioning of symptomatic patients with severe aortic stenosis, regardless of age. If the aortic stenosis is above the 'severe' threshold, the degree of stenosis does not predict disease burden. These results encourage to reconsider a conservative approach in symptomatic patients with severe aortic stenosis. Using the SF-36v2 Health Survey together with this study, an individual patient's quality of life profile can be assessed and compared with the patient group or with the general population. This can assist in decision making for the individual patient.

Comparing cost aspects of coronary artery bypass graft surgery with coronary artery stenting.

Randomized trials have compared revascularization of coronary artery disease by coronary artery bypass graft surgery (CABG) or percutaneous coronary intervention (PCI). CABG is an expensive treatment. However, it manages to improve quality of life, restore general well being, and alleviate symptoms of patients. Coronary stents have improved the safety and durability of PCI. Nonetheless, stenting remains limited by a relatively high in-stent restenosis and thrombosis rate. The costs and cost-effectiveness for these different treatment modalities are relevant issues because cardiovascular disease and its management are prime targets for cost reduction initiatives. There is a debate as to which is the optimal treatment strategy as well as to the cost-effectiveness comparing CABG and PCI. This review provides an overview of cost-effectiveness of CABG compared with PCI. PCI has high costs due to the need for subsequent revascularization procedures, with absence of mortality and survival benefit compared with CABG. Despite the relative lower initial costs of PCI in the first year, PCI is not a cost-effective intervention in comparison with CABG. However, the studies undertaken to date have predominantly been short term and provide a very limited evidence base by which to assess the cost-effectiveness of modern clinical practice. It seems that in longer term, the benefits of CABG may exceed those of stenting and the difference in net cost may be in favour of CABG as the risk of repeat revascularization still increases with PCI regardless of the use of DES. However, to date no long-term data are available in cost-effectiveness between CABG and PCI. The 5-year outcome of the ongoing SYNTAX trial is essential and might therefore provide new insights into the comparison of cost-effectiveness between CABG and DES PCI.

Aortic root reoperations after pulmonary autograft implantation.

OBJECTIVE: To report the results of aortic root reoperations after pulmonary autograft implantation. METHODS: All consecutive patients in our prospective Ross research database were selected for analysis, and additional information for patients requiring reoperation was obtained from the hospital records. RESULTS: From 1988 to 2009, 155 pulmonary autograft operations were performed. During this period, 41 patients required reoperation for aortic root dilatation and/or autograft valve insufficiency, in 8 patients combined with pulmonary allograft dysfunction. The freedom from autograft reoperation rate was 86% (standard error, 3.3%) after 10 years and 52% (standard error, 6.6%) after 15 years. The median interval to reoperation was 15.3 years. During reoperation, 39 patients underwent aortic root replacement (mechanical conduit, 31; stentless root, 2; allograft, 3; and valve sparing, 3), and 2 patients underwent valve replacement. In 8 patients this was combined with pulmonary allograft replacement. The technical difficulties encountered included bleeding at the sternal re-entry in 5 patients. No 30-day mortality occurred. The postoperative complications included reexploration for persistent blood loss in 3 patients and cerebrovascular accident in 3 patients. Two patients died during the follow-up period. The survival rate after reoperation was 94% (standard error, 4.1%) at 5 years. CONCLUSIONS: An increasing number of patients requires reoperation after pulmonary autograft implantation. These reoperations can be done with very low mortality and morbidity and excellent follow-up results.

Impact of the definition of renal dysfunction on EuroSCORE performance.

AIM: Renal dysfunction is an important variable in the EuroSCORE (European System for Cardiac Operative Risk Evaluation) model and is currently defined as creatinine >200 mmol/L. The aim of this study was to examine whether using other definitions of renal dysfunction could improve the predictive ability of the EuroSCORE. METHODS: Between January 2004 and January 2006, 1 205 patients underwent cardiac surgery. Their preoperative glomerular filtration rate and EuroSCORE were calculated. Four recalibrated EuroSCORE models were constructed using 1) creatinine as a binary variable; 2) creatinine as a continuous variable; 3) glomerular filtration rate as a categorical variable; or 4) glomerular filtration rate as a continuous variable. The predictive ability of these models was assessed using receiver operating characteristic curve analysis. RESULTS: Hospital mortality was 4% (N.=47). Receiver operating characteristic curve values were: 0.78 for the original EuroSCORE, 0.80 for the recalibrated binary creatinine model, 0.83 for the continuous creatinine model, 0.83 for the categorical glomerular filtration rate model, and 0.82 for the continuous glomerular filtration rate model. CONCLUSIONS: The use of creatinine as a continuous variable or glomerular filtration rate as a categorical or continuous variable improves the predictive accuracy of the EuroSCORE model for hospital mortality. Given the increasing incidence of preoperative renal dysfunction and its impact on hospital mortality, future risk stratification models should include continuous creatinine or glomerular filtration rate rather than creatinine as a binary variable.

Preserved hyperaemic response in supraclavicular ultrasonography demonstrates function on demand of the LIMA to LAD string sign graft after CABG.

AIM: To correlate supraclavicular ultrasonography with angiographically patent and string sign left internal mammary artery (LIMA) to left anterior descending artery (LAD) grafts. METHODS: Sixteen patients with a single LIMA anastomosis to the LAD were prospectively entered in a follow-up study. The supraclavicular ultrasonography of the LIMA origin was studied preoperatively and at 5.3+/-3.6 months and 1.7+/-0.4 year postoperatively. At the late postoperative ultrasonography electrocardiographically controlled hyperemic response was also studied for 6 min. Control angiography was performed at 1.5+/-0.8 year. Differences within groups were tested with a paired t-test and between groups with an unpaired t-test. RESULTS: Control angiography showed in 13 patients (group I) a patent LIMA graft and in 3 patients (group II) a string sign LIMA graft. Preoperative blood velocities were not significantly different between groups. Postoperatively, both groups revealed higher diastolic and lower systolic blood velocities compared to preoperative values. The blood velocities at rest did not change in group I and all velocities decreased in group II in time postoperatively. The blood velocities in maximal hyperemic response increased significantly within the groups and were not significantly different between the groups. No ischemia could be detected electrocardiographically during hyperemic response and no patient presented angina. CONCLUSIONS: Both groups showed a shift towards coronary type diastolic blood velocities at rest and at hyperaemic response. Significant hyperemic response was also present in string sign LIMA grafts and demonstrates response capacity to increased myocardial oxygen demand.

Long-term outcome after surgery for pulmonary stenosis (a longitudinal study of 22-33 years).

AIMS: Long-term (>20 years) survival and clinical outcome are only partly documented in patients who underwent surgical repair for isolated pulmonary stenosis. Yet, such data are of critical importance for the future perspectives, medical care, employability, and insurability of these patients. METHODS AND RESULTS: Ninety consecutive patients underwent surgery for pulmonary stenosis between 1968 and 1980 at the Thoraxcenter. A systematic follow-up study was performed in 1990 and again in 2001. Survival after 25 years was 93%. Re-intervention was necessary in 15% of the patients, mainly for pulmonary regurgitation. Right atrial and ventricular dilatation and paradoxical septal motion were associated with the need for reoperation. No major ventricular arrhythmias occurred. Supraventricular arrhythmias occurred, only in patients with severe pulmonary regurgitation and disappeared after reoperation. At last follow-up, 67% of the patients was in NYHA Class I and maximal exercise capacity was 90% of normal. Moderate or severe pulmonary regurgitation was present in 37% of the patients. CONCLUSION: Although long-term survival and quality of life are good, pulmonary regurgitation is found in a third of the patients 22-33 years after surgical repair for isolated pulmonary stenosis and reoperation for pulmonary regurgitation was necessary in 9%, especially after the transannular patch technique.

Prognostic factors in non-small cell lung cancer surgery.

AIMS: Complete surgical resection of primary tumours remains the treatment with the greatest likelihood for survival in early-stage non-small cell lung cancer (NSCLC). Although TNM stage is the most important prognostic parameter in NSCLC, additional parameters are required to explain the large variability in postoperative outcome. The present review aims at providing an overview of the currently known prognostic markers for postoperative outcome. METHODS: We performed an electronic literature search on the MEDLINE database to identify relevant studies describing the risk factors in NSCLC surgery. The references reported in all the identified studies were used for completion of the literature search. RESULTS: Poor pulmonary function, cardiovascular disease, male gender, advanced age, TNM stage, non-squamous cell histology, pneumonectomy, low hospital volume and little experience of the surgeon were identified as risk factors for postoperative outcome. However, with the exception of TNM stage and extent of resection, the literature demonstrates conflicting results on the prognostic power of most factors. The role of molecular biological factors, neoadjuvant treatment and adjuvant treatment is not well investigated yet. CONCLUSIONS: The advantage of knowing about the existence of comorbidity and prognostic risk factors may provide the clinician with the ability to identify poor prognostic patients and establish the most appropriate treatment strategy. The assessment of prognostic factors remains an area of active investigation and a promising field of research in optimising therapy of NSCLC patients.

Contrast enhancement of coronary arteries in cardiac surgery: a new multispectral stereoscopic camera technique.

OBJECTIVE: During open heart surgery, the myocardium usually provides sufficient visual contrast with both epicardial veins and arteries. However, visibility of coronary arteries may occasionally be impaired due to, e.g., intra-myocardial course of coronary arteries, increased epicardial fat, epicardial post-surgical adhesions, or pericarditis. Seen within the near infra-red range, coronary arteries show higher contrasts in relation to the myocardium than coronary veins. Hence, we developed a non-contact stereo-optical camera to selectively enhance coronary arteries by combining visible and near infra-red images. In this paper we present our first results on porcine and human hearts. MATERIALS AND METHODS: Two CMOS-cameras, with apochromatic lenses and dual-band LED-arrays, -captured visible colour (visible range, or VIS, 400-780nm) and near infra-red grey-scale (near infra-red range, or NIR, 910-920nm) images by sequentially switching between LED-array emission bands. Data was recorded by computer and processed off-line. Arterial NIR contrasts were algorithmically distinguished from shadows and specular reflections. Detected arteries were selectively enhanced and back-projected into the stereoscopic VIS-colour-image using either a 3D-display or conventional shutter glasses. RESULTS: Our technique visualised coronary vasculature and allowed to identify concealed parts of coronary arteries using off-line processing. Raw VIS & NIR images were real-time, processing took < 15s after filming. CONCLUSION: The applied principle works, but needs further development.

Proinflammatory cytokines upregulate mRNA expression and secretion of vascular endothelial growth factor in cultured human airway smooth muscle cells.

Airflow obstruction in chronic airway disease is associated with airway and pulmonary vascular remodeling, of which the molecular mechanisms are poorly understood. Paracrine actions of angiogenic factors released by resident or infiltrating inflammatory cells following activation by proinflammatory cytokines in diseased airways could play a major role in the airway vascular remodeling process. Here, the proinflammatory cytokines interleukin (IL)-1beta, and tumor necrosis factor (TNF)-alpha were investigated on cell cultures of human airway smooth muscle (ASM) for their effects on mRNA induction and protein release of the angiogenic peptide, vascular endothelial growth factor (VEGF). IL-1beta (0.5 ng/mL) and TNF-alpha (10 ng/mL) each increased VEGF mRNA (3.9 and 1.7 kb) expression in human ASM cells, reaching maximal levels between 16 and 24 and 4 and 8 h, respectively. Both cytokines also induced a time-dependent release of VEGF, which was not associated with increased ASM growth. Preincubation of cells with 1 microM dexamethasone abolished enhanced release of VEGF by TNF-alpha. The data suggest that human ASM cells express and secrete VEGF in response to proinflammatory cytokines and may participate in paracrine inflammatory mechanisms of vascular remodeling in chronic airway disease.